Plasma-derived blood products are used to treat not only a variety of blood disorders, but diseases of other origin. For example, immune globulin (IgG) products from human plasma were first used in 1952 to treat immune deficiency. Since then, IgG preparations have found widespread use in at least three main categories of medical conditions: (1) immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies), featuring low antibody levels; (2) inflammatory and autoimmune diseases; and (3) acute infections.
Various safety precautions must be taken into consideration when manufacturing and formulating plasma-derived biologic therapies. These precautions include methods for removing and/or inactivating blood borne pathogens (e.g., viral and bacterial pathogens), anti-complement activity, and other unwanted contaminants arising from the use of donated plasma. Studies have suggested that administration of high levels of amidolytic activity may result in unwanted thromboembolic events (Wolberg A S et al., Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30-34; and Alving B M et al., Contact-activated factors: contaminants of immunoglobulin preparations with coagulant and vasoactive properties. J Lab Clin Med 1980; 96:334-346; the disclosures of which are hereby incorporated by reference in their entireties for all purposes).
Highlighting this concern was the voluntary withdrawal of Octagam® (Octapharma) in the US and suspension of marketing authorization for Octagam® and Octagam 10% by the European Commission following increased reports of thromboembolic events. It has been suggested that the increased thrombolic events were caused by high levels of amidolytic activity in the biologic, caused by serine protease and serine protease zymogen impurities, such as Factor XI, Factor XIa, Factor XII and Factor XIIa (FDA Notice: Voluntary Market Withdrawal—Sep. 23, 2010 Octagam [Immune Globulin Intravenous (Human)] 5% Liquid Preparation; Octagam 50 mg/ml, solution pour perfusion—Octapharma France—Mise en quarantaine de tous les lots, published online Sep. 9, 2010 by the AFSSAPS; and Questions and answers on the suspension of the marketing authorizations for Octagam (human normal immunoglobulin 5% and 10%), published online Sep. 23, 2010 by the European Medicines Agency).
The EDQM (European Directorate on the Quality of Medicines & Health Care) published a revision of the monograph for human normal immunoglobulin for intravenous administration (0918) for rapid implementation on Jan. 1, 2012 to address the potential pro-coagulant activity in immune globulin products. The revision states that “[t]he method of preparation also includes a step or steps that have been shown to remove thrombosis-generating agents. Emphasis is given to the identification of activated coagulation factors and their zymogens and process steps that may cause their activation. Consideration is also to be given to other procoagulant agents that could be introduced by the manufacturing process.”
On Mar. 18, 2011, Swissmedic reported that thromboembolic adverse events have been seen in association with numerous Vivaglobin product lots by FDA. Vivaglobin (160 mg/mL human normal immunoglobulin solution for subcutaneous injection), manufactured by CSL was licensed as replacement therapy for adults and children with primary immunodeficiency syndromes, myeloma, or chronic lymphatic leukemia. The risk of thromboembolic adverse events was not known until this time for this route of administration. Investigations revealed pro-coagulant activity at least in some batches. As a consequence, Vivaglobin was withdrawn from the market and replaced by the new product Hizentra (20% human normal immunoglobulin solution for subcutaneous injection). Due to the adverse events reported for Vivaglobin, it now a requirement that immunoglobulin products for subcutaneous administration have low levels of procoagulant activity, similar to the requirements for intravenous immunoglobulin products.
Dedicated serine proteases, generically known as coagulation factors, are integral components of both the contact activation and tissue factor pathways of the coagulation cascade. Upon a stimulus of the coagulation pathways, serine protease zymogens, which are inactive enzyme precursors, become activated proteases that catalyze the activation of the next protease zymogen, resulting in an activation cascade. This coagulation cascade culminates in the activation of Thrombin (Factor IIa) and Factor XIIIa, which function to convert Fibrinogen (Factor I) into Fibrin (Factor Ia) and cross-link fibrin to form a fibrin clot, respectively.
The contact activation pathway, also known as the intrinsic coagulation pathway, begins with the activation of Kallikrein and Factor XIIa (FXIIa) from Prekallikrein and Factor XII, respectively. The activated serine protease FXIIa cleaves Factor XI (FXI), converting the zymogen into Factor XIa (FXIa), an active serine protease which participates in the subsequent activation of Factor Xa (FXa).
Due to rising concerns over the presence of serine protease and serine protease zymogens in plasma-derived protein compositions, there remains a need in the art for methods for reducing the levels of these contaminants, and particularly FXI and FXIa, in immunoglobulin preparations.